Due to spreading resistances, new drugs against malaria are continuously needed in poor countries where severe malaria kills millions of children every year. Ethical drugs must be cheap and therefore they should be easy to synthesize if they are not readily available as chemicals on the market.
Plasmodium parasites are exposed to elevated fluxes of reactive oxygen species during the life cycle in the human host and therefore high activities of intracellular antioxidant systems are needed. The most important antioxidative system consists of thiols which are regenerated by disulfide reductases; these include three validated drug targets, the glutathione reductases (GR) of the malarial parasite Plasmodium falciparum and of human erythrocytes as well as the thioredoxin reductase of P. falciparum (Schirmer et al, Angew. Chem. Int. Ed. Engl. 1995, 34, 141-54; Krauth-Siegel et al, Angewandte Chemie International Edition (2005), 44 (5), 690-715). One validated target against the malarial parasite Plasmodium falciparum is the enzyme glutathione reductase which reduces glutathione disulfide to its thiol form glutathione on the expense of NADPH. Glutathione is implicated in the development of chloroquine resistance: an elevation of the glutathione content in P. falciparum leads to increased resistance to chloroquine, while glutathione depletion in resistant strains restores sensitivity to chloroquine (Meierjohan et al, Biochem. J. 2002, 368, 761-768). High intracellular glutathione levels depend inter alia on the efficient reduction of glutathione disulfide by GR and by reduced thioredoxin (Kanzok et al, Science 2001, 291, 643-646). The contribution to the reversal of drug resistance by GR inhibitors is currently investigated for the commonly used antimalarial drug chloroquine in clinical trials (Sarma et al., J. Mol. Biol. 2003, 328, 893-907). Derivatives of menadione were shown to be potent inhibitors both of human and Plasmodium falciparum glutathione reductases acting in the low micromolar range (Davioud-Charvet et al, J. Med. Chem. 2001, 44, 4268-4276; Biot et al, J. Med. Chem. 47, 5972-5983; Bauer et al, J. Am. Chem. Soc. 2006, 128, 10784-10794).
The malarial parasite Plasmodium falciparum digests a large amount of its host cell hemoglobin during its erythrocytic cycle as source of essential nutrients (Zarchin et al, Biochem. Pharmacol. 1986, 35, 2435-2442). The digestion is a complex process that involves several proteases and takes place in the food vacuole of the parasite leading to the formation of iron III ferroprotoporphyrin (FPIX) (Goldberg et al, Parasitol. Today, 1992, 8, 280-283) as toxic byproduct for the parasite. Due to the toxicity of FPIX the parasites have developed a detoxification process in which FPIX (Fe3+) (hematin) is polymerized forming inert crystals of hemozoin or malaria pigment (Dorn et al, Nature 1995, 374, 269-271). FPIX (Fe2+) is an inhibitor of hematin polymerization (Monti et al, Biochemistry 1999, 38, 8858-8863). Early observations indicated that free FPIX (Fe3+) is able to form complexes with aromatic compounds bearing nitrogen, e.g. pyridines, 4-aminoquinolines (Cohen et al, Nature 1964, 202, 805-806; Egan et al, J. Inorg. Biochem. 2006, 100, 916-926) and it is now well established that 4-aminoquinolines can form μ-oxodimers with FPIX thus preventing the formation of hemozoin. Consequently an accumulation of free heme in the food vacuole is responsible for killing the parasite (Vippagunta et al, Biomed. Biochim. Acta 2000, 1475, 133-140). In the presence of reactive oxygen species iron-porphyrin complexes (e.g. free heme) are catalysts for oxidation reactions. Released in large quantities in the food vacuole of the parasite they are thought to strongly influence the activity of a drug under the specific acidic conditions of the malarial food vacuole. Drug metabolites can be more active than its precursor (pro-drug effect) or toxic (Bernadou et al, Adv. Synth. Catal. 2004, 346, 171-184).
The reduction of methemoglobin(Fe3+) into hemoglobin(Fe2+) is of great importance in the treatment of malaria. Since the malarial parasite is much more capable of using methemoglobin as nutrient and digests methemoblobin faster than hemoglobin, the reduction of methemoglobin can be used to slow down the parasite's methemoglobin digestion by reducing its concentration. A second reason to target the reduction of methemoglobin is that methemoglobin, the ferric form of hemoglobin, is not capable of oxygen transport. High levels of methemoglobin are found during Plasmodium vivax infections (Anstey et al, Trans. R. Soc. Trop. Med. Hyg. 1996, 90, 147-151). A reduced oxygen carrying capacity of blood due to anaemia is even worsened by reduction in oxygen carrying capacity from even a modest concentration of methemoglobin leading to an impaired supply of oxygen for the tissue; a specific situation observed in cerebral malaria.
Since the malarial parasite Plasmodium falciparum multiplies in human erythrocytes, most drugs are directed against this stage of the life cycle of the parasite. Due to increasing resistance of the parasite against standard drugs such as chloroquine, newly drugs are urgently required.
There is therefore still a need for compounds having efficiency against malaria, without their usual drawbacks. Furthermore, there is a need for anti-malarial drugs which are easy to formulate in pharmaceutical compositions.